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Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

CiteScore 2017: 2.48

SCImago Journal Rank (SJR) 2017: 1.021
Source Normalized Impact per Paper (SNIP) 2017: 0.830

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Volume 30, Issue 1


Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Albert Pérez-Martí
  • Department of Nutrition, Food Sciences and Gastronomy, Food Campus (Torribera), School of Pharmacy, University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain
  • Institute of Biomedicine from University of Barcelona (IBUB), Barcelona, Spain
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Viviana Sandoval
  • Department of Nutrition, Food Sciences and Gastronomy, Food Campus (Torribera), School of Pharmacy, University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain
  • Institute of Biomedicine from University of Barcelona (IBUB), Barcelona, Spain
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Pedro F. Marrero
  • Department of Nutrition, Food Sciences and Gastronomy, Food Campus (Torribera), School of Pharmacy, University of Barcelona, Santa Coloma de Gramenet, Barcelona, Spain
  • Institute of Biomedicine from University of Barcelona (IBUB), Barcelona, Spain
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Diego Haro
  • Corresponding author
  • Institute of Biomedicine from University of Barcelona (IBUB), Barcelona, Spain
  • Department of Nutrition, Food Sciences and Gastronomy, Food Campus (Torribera), School of Pharmacy, University of Barcelona, Av Prat de la Riba 171, 08921 Santa Coloma de Gramenet, Barcelona, Spain
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Joana Relat
  • Corresponding author
  • Institute of Biomedicine from University of Barcelona (IBUB), Barcelona, Spain
  • Department of Nutrition, Food Sciences and Gastronomy, Food Campus (Torribera), School of Pharmacy, University of Barcelona, Av Prat de la Riba 171, 08921 Santa Coloma de Gramenet, Barcelona, Spain
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-09-01 | DOI: https://doi.org/10.1515/hmbci-2016-0034


Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21- KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existing information about the mechanisms that could allow the control of endogenous FGF21 levels in order to obtain the beneficial metabolic effects of FGF21 by inducing its production instead of doing it by pharmacological administration.

Keywords: beta-klotho; diet; energy metabolism; fibroblast growth factor 21; obesity


  • 1.

    Kharitonenkov A, Shanafelt AB. FGF21: a novel prospect for the treatment of metabolic diseases. Curr Opin Investig Drugs 2009;10:359–64.PubMedGoogle Scholar

  • 2.

    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627–35.CrossrefPubMedGoogle Scholar

  • 3.

    Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013;18:333–40.PubMedCrossrefGoogle Scholar

  • 4.

    Weng Y, Chabot JR, Bernardo B, Yan Q, Zhu Y, Brenner MB, Vage C, Logan A, Calle R, Talukdar S. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. PLoS One 2015;10:e0119104.PubMedCrossrefGoogle Scholar

  • 5.

    Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab 2016;23:427–40.PubMedCrossrefGoogle Scholar

  • 6.

    Chu AY, Workalemahu T, Paynter NP, Rose LM, Giulianini F, Tanaka T, Ngwa JS; CHARGE Nutrition Working Group, Qi Q, Curhan GC, Rimm EB, Hunter DJ, Pasquale LR, Ridker PM, Hu FB, Chasman DI, Qi L; DietGen Consortium. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet 2013;22:1895–902.PubMedCrossrefGoogle Scholar

  • 7.

    Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Münzberg H, Hutson SM, Gettys TW, Schwartz MW, Morrison CD. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014;124:3913–22.PubMedCrossrefGoogle Scholar

  • 8.

    Dushay J, Chui PC, Gopalakrishnan GS, Varela-Rey M, Crawley M, Fisher FM, Badman MK, Martinez-Chantar ML, Maratos-Flier E. Increased fibroblast growth factor 21 in obesity and nonalcoholic fatty liver disease. Gastroenterology 2010;139:456–63.CrossrefPubMedGoogle Scholar

  • 9.

    Itoh N. FGF21 as a hepatokine, adipokine, and myokine in metabolism and diseases. Front Endocrinol (Lausanne) 2014;5:107.PubMedGoogle Scholar

  • 10.

    Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One 2012;7:e33870.CrossrefPubMedGoogle Scholar

  • 11.

    Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ, Kliewer SA. betaKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012;16:387–93.CrossrefPubMedGoogle Scholar

  • 12.

    Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol 2016;78:223–41.PubMedCrossrefGoogle Scholar

  • 13.

    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab 2007;5:415–25.CrossrefPubMedGoogle Scholar

  • 14.

    Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 2009;106:10853–8.CrossrefGoogle Scholar

  • 15.

    Dasarathy S, Yang Y, McCullough AJ, Marczewski S, Bennett C, Kalhan SC. Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis. Eur J Gastroenterol Hepatol 2011;23:382–8.PubMedCrossrefGoogle Scholar

  • 16.

    Domingo P, Gallego-Escuredo JM, Domingo JC, Gutiérrez Mdel M, Mateo MG, Fernández I, Vidal F, Giralt M, Villarroya F. Serum FGF21 levels are elevated in association with lipodystrophy, insulin resistance and biomarkers of liver injury in HIV-1-infected patients. AIDS 2010;24:2629–37.PubMedCrossrefGoogle Scholar

  • 17.

    Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008;57:1246–53.PubMedCrossrefGoogle Scholar

  • 18.

    Yang C, Lu W, Lin T, You P, Ye M, Huang Y, Jiang X, Wang C, Wang F, Lee MH, Yeung SC, Johnson RL, Wei C, Tsai RY, Frazier ML, McKeehan WL, Luo Y. Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 2013;13:67.PubMedCrossrefGoogle Scholar

  • 19.

    Fisher FM, Estall JL, Adams AC, Antonellis PJ, Bina HA, Flier JS, Kharitonenkov A, Spiegelman BM, Maratos-Flier E. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology 2011;152:2996–3004.CrossrefPubMedGoogle Scholar

  • 20.

    De Sousa-Coelho AL, Relat J, Hondares E, Pérez-Martí A, Ribas F, Villarroya F, Marrero PF, Haro D. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res 2013;54:1786–97.CrossrefPubMedGoogle Scholar

  • 21.

    Hotta Y, Nakamura H, Konishi M, Murata Y, Takagi H, Matsumura S, Inoue K, Fushiki T, Itoh N. Fibroblast growth factor 21 regulates lipolysis in white adipose tissue but is not required for ketogenesis and triglyceride clearance in liver. Endocrinology 2009;150:4625–33.PubMedCrossrefGoogle Scholar

  • 22.

    Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK, Takahashi JS, Mangelsdorf DJ, Kliewer SA. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013;19:1147–52.PubMedCrossrefGoogle Scholar

  • 23.

    Ishida N. Role of PPAR in the control of torpor through FGF21-NPY pathway: from circadian clock to seasonal change in mammals. PPAR Res 2009;2009:412949.PubMedGoogle Scholar

  • 24.

    Li X, Ge H, Weiszmann J, Hecht R, Li YS, Véniant MM, Xu J, Wu X, Lindberg R, Li Y. Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob/ob mice. FEBS Lett 2009;583:3230–4.PubMedCrossrefGoogle Scholar

  • 25.

    Arner P, Pettersson A, Mitchell PJ, Dunbar JD, Kharitonenkov A, Ryden M. FGF21 attenuates lipolysis in human adipocytes – a possible link to improved insulin sensitivity. FEBS Lett 2008;582:1725–30.CrossrefPubMedGoogle Scholar

  • 26.

    Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 2012;148:556–67.CrossrefPubMedGoogle Scholar

  • 27.

    Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states. Mol Pharmacol 2008;74:403–12.PubMedCrossrefGoogle Scholar

  • 28.

    Ge X, Chen C, Hui X, Wang Y, Lam KSL, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. J Biol Chem 2011;286:34533–41.PubMedCrossrefGoogle Scholar

  • 29.

    Camporez JP, Jornayvaz FR, Petersen MC, Pesta D, Guigni BA, Serr J, Zhang D, Kahn M, Samuel VT, Jurczak MJ, Shulman GI. Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice. Endocrinology 2013;154:3099–109.CrossrefPubMedGoogle Scholar

  • 30.

    Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013;17:779–89.PubMedCrossrefGoogle Scholar

  • 31.

    Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC, Volk K, Kuo MS, Gordillo R, Kharitonenkov A, Scherer PE. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 2013;17:790–7.PubMedCrossrefGoogle Scholar

  • 32.

    Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271–81.CrossrefPubMedGoogle Scholar

  • 33.

    Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983–90.PubMedCrossrefGoogle Scholar

  • 34.

    Chartoumpekis DV, Habeos IG, Ziros PG, Psyrogiannis AI, Kyriazopoulou VE, Papavassiliou AG. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011;17:736–40.PubMedGoogle Scholar

  • 35.

    Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010;11:206–12.CrossrefPubMedGoogle Scholar

  • 36.

    Samms RJ, Smith DP, Cheng CC, Antonellis PP, Perfield JW, Kharitonenkov A, Gimeno RE, Adams AC. Discrete aspects of FGF21 in vivo pharmacology do not require UCP1. Cell Rep 2015;11:991–9.CrossrefPubMedGoogle Scholar

  • 37.

    Véniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ. Pharmacologic effects of FGF21 are independent of the “Browning” of white adipose tissue. Cell Metab 2015;21:731–8.CrossrefPubMedGoogle Scholar

  • 38.

    Bernardo B, Lu M, Bandyopadhyay G, Li P, Zhou Y, Huang J, Levin N, Tomas EM, Calle RA, Erion DM, Rolph TP, Brenner M, Talukdar S. FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance. Sci Rep 2015;5:11382.CrossrefPubMedGoogle Scholar

  • 39.

    Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett 2008;582:3805–10.PubMedCrossrefGoogle Scholar

  • 40.

    Hojman P, Pedersen M, Nielsen AR, Krogh-Madsen R, Yfanti C, Akerstrom T, Nielsen S, Pedersen BK. Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia. Diabetes 2009;58:2797–801.PubMedCrossrefGoogle Scholar

  • 41.

    Kim KH, Kim SH, Min Y-K, Yang H-M, Lee J-B, Lee M-S. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 2013;8:e63517.PubMedCrossrefGoogle Scholar

  • 42.

    Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T, Ruhanen H, Guse K, Hemminki A, Peltola-Mjøsund KE, Tulkki V, Oresic M, Moraes CT, Pietiläinen K, Hovatta I, Suomalainen A. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 2010;19:3948–58.CrossrefPubMedGoogle Scholar

  • 43.

    Vandanmagsar B, Warfel JD, Wicks SE, Ghosh S, Salbaum JM, Burk D, Dubuisson OS, Mendoza TM, Zhang J, Noland RC, Mynatt RL. Impaired mitochondrial fat oxidation induces FGF21 in muscle. Cell Rep 2016;15:1686–99.CrossrefPubMedGoogle Scholar

  • 44.

    Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim do H, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013;19:83–92.CrossrefPubMedGoogle Scholar

  • 45.

    Harris L-ALS, Skinner JR, Shew TM, Pietka TA, Abumrad NA, Wolins NE. Perilipin 5-driven lipid droplet accumulation in skeletal muscle stimulates the expression of fibroblast growth factor 21. Diabetes 2015;64:2757–68.PubMedCrossrefGoogle Scholar

  • 46.

    Keipert S, Ost M, Johann K, Imber F, Jastroch M, van Schothorst EM, Keijer J, Klaus S. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014;306:E469–82.PubMedCrossrefGoogle Scholar

  • 47.

    Lee MS, Choi SE, Ha ES, An SY, Kim TH, Han SJ, Kim HJ, Kim DJ, Kang Y, Lee KW. Fibroblast growth factor-21 protects human skeletal muscle myotubes from palmitate-induced insulin resistance by inhibiting stress kinase and NF-kappaB. Metabolism 2012;61:1142–51.PubMedCrossrefGoogle Scholar

  • 48.

    Mashili FL, Austin RL, Deshmukh AS, Fritz T, Caidahl K, Bergdahl K, Zierath JR, Chibalin AV, Moller DE, Kharitonenkov A, Krook A. Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity. Diabetes Metab Res Rev 2011;27:286–97.PubMedCrossrefGoogle Scholar

  • 49.

    Brahma MK, Adam RC, Pollak NM, Jaeger D, Zierler KA, Pöcher N, Schreiber R, Romauch M, Moustafa T, Eder S, Ruelicke T, Preiss-Landl K, Lass A, Zechner R, Haemmerle G. Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis. J Lipid Res 2014;55:2229–41.CrossrefPubMedGoogle Scholar

  • 50.

    Planavila A, Redondo-Angulo I, Villarroya F. FGF21 and cardiac physiopathology. Front Endocrinol 2015;6:133.Google Scholar

  • 51.

    Dogan SA, Pujol C, Maiti P, Kukat A, Wang S, Hermans S, Senft K, Wibom R, Rugarli EI, Trifunovic A. Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart. Cell Metab 2014;19:458–69.CrossrefPubMedGoogle Scholar

  • 52.

    Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M, Villarroya F. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res 2014;106:19–31.PubMedGoogle Scholar

  • 53.

    Liu SQ, Roberts D, Kharitonenkov A, Zhang B, Hanson SM, Li YC, Zhang LQ, Wu YH. Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue. Sci Rep 2013;3:2767.PubMedCrossrefGoogle Scholar

  • 54.

    Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K, Kambara T, Uemura Y, Hayakawa S, Hiramatsu-Ito M, Kanemura N, Ogawa H, Daida H, Murohara T, Ouchi N. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochem Biophys Res Commun 2015;459:124–30.CrossrefPubMedGoogle Scholar

  • 55.

    Fon Tacer K, Bookout AL, Ding X, Kurosu H, John GB, Wang L, Zhang LQ, Wu YH. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol Endocrinol 2010;24:2050–64.CrossrefPubMedGoogle Scholar

  • 56.

    Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, Ding H, Lam KS, Xu A. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014;63:4064–75.CrossrefPubMedGoogle Scholar

  • 57.

    Mäkelä J, Tselykh TV, Maiorana F, Eriksson O, Do HT, Mudò G, Korhonen LT, Belluardo N, Lindholm D. Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1alpha in human dopaminergic neurons via Sirtuin-1. Springerplus 2014;3:2.PubMedCrossrefGoogle Scholar

  • 58.

    Tan BK, Hallschmid M, Adya R, Kern W, Lehnert H, Randeva HS. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes 2011;60:2758–62.CrossrefPubMedGoogle Scholar

  • 59.

    Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, Kliewer SA, Mangelsdorf DJ. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 2013;19:1153–6.CrossrefPubMedGoogle Scholar

  • 60.

    Douris N, Stevanovic D, Fisher FM, Cisu TI, Chee MJ, Ly Nguyen N, Zarebidaki E, Adams AC, Kharitonenkov A, Flier JS, Bartness TJ, Maratos-Flier E. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015;156:2470–81.CrossrefPubMedGoogle Scholar

  • 61.

    Owen BM, Bookout AL, Ding X, Lin VY, Atkin SD, Gautron L, Kliewer SA, Mangelsdorf DJ. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014;20:670–7.CrossrefPubMedGoogle Scholar

  • 62.

    Arase K, York D, Shimizu H, Shargill N, Bray G. Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats. Am J Physiol 1988;255:255–9.Google Scholar

  • 63.

    Johnson CL, Weston JY, Chadi SA, Fazio EN, Huff MW, Kharitonenkov A, Köester A, Pin CL. Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice. Gastroenterology 2009;137:1795–804.PubMedCrossrefGoogle Scholar

  • 64.

    Uonaga T, Toyoda K, Okitsu T, Zhuang X, Yamane S, Uemoto S, Inagaki N. FGF-21 enhances islet engraftment in mouse syngeneic islet transplantation model. Islets 2010;2:247–51.CrossrefPubMedGoogle Scholar

  • 65.

    Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006;55:2470–8.PubMedCrossrefGoogle Scholar

  • 66.

    So WY, Cheng Q, Chen L, Evans-Molina C, Xu A, Lam KS, Leung PS. High glucose represses beta-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor gamma signaling. Diabetes 2013;62:3751–9.PubMedCrossrefGoogle Scholar

  • 67.

    Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 2012;1:1–14.Google Scholar

  • 68.

    von Holstein-Rathlou S, BonDurant LD, Peltekian L, Naber MC, Yin TC, Claflin KE, Urizar AI, Madsen AN, Ratner C, Holst B, Karstoft K, Vandenbeuch A, Anderson CB, Cassell MD, Thompson AP, Solomon TP, Rahmouni K, Kinnamon SC, Pieper AA, Gillum MP, Potthoff MJ. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 2016;23:335–43.CrossrefPubMedGoogle Scholar

  • 69.

    Talukdar S, Owen BM, Song P, Hernandez G, Zhang Y, Zhou Y, Scott WT, Paratala B, Turner T, Smith A, Bernardo B, Müller CP, Tang H, Mangelsdorf DJ, Goodwin B, Kliewer SA. FGF21 regulates sweet and alcohol preference. Cell Metab 2016;23:344–9.PubMedCrossrefGoogle Scholar

  • 70.

    Tanaka T, Ngwa JS, van Rooij FJ, Zillikens MC, Wojczynski MK, Frazier-Wood AC, Houston DK, Kanoni S, Lemaitre RN, Luan J, Mikkilä V, Renstrom F, Sonestedt E, Zhao JH, Chu AY, Qi L, Chasman DI, de Oliveira Otto MC, Dhurandhar EJ, Feitosa MF, Johansson I, Khaw KT, Lohman KK, Manichaikul A, McKeown NM, Mozaffarian D, Singleton A, Stirrups K, Viikari J, Ye Z, Bandinelli S, Barroso I, Deloukas P, Forouhi NG, Hofman A, Liu Y, Lyytikäinen LP, North KE, Dimitriou M, Hallmans G, Kähönen M, Langenberg C, Ordovas JM, Uitterlinden AG, Hu FB, Kalafati IP, Raitakari O, Franco OH, Johnson A, Emilsson V, Schrack JA, Semba RD, Siscovick DS, Arnett DK, Borecki IB, Franks PW, Kritchevsky SB, Lehtimäki T, Loos RJ, Orho-Melander M, Rotter JI, Wareham NJ, Witteman JC, Ferrucci L, Dedoussis G, Cupples LA, Nettleton JA. Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. Am J Clin Nutr 2013;97:1395–402.CrossrefPubMedGoogle Scholar

  • 71.

    Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, Goetz R, Mohammadi M, Gerard RD, Dechow PC, Mangelsdorf DJ, Kliewer SA, Wan Y. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci USA 2012;109:3143–8.CrossrefGoogle Scholar

  • 72.

    Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, Mohammadi M, Potthoff MJ. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014;63:4057–63.CrossrefPubMedGoogle Scholar

  • 73.

    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426–37.CrossrefPubMedGoogle Scholar

  • 74.

    Lundåsen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M. PPARα is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 2007;360:437–40.CrossrefPubMedGoogle Scholar

  • 75.

    Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor a to regulate metabolic hormone FGF21. Endocrinology 2014;155:769–82.CrossrefGoogle Scholar

  • 76.

    Lee JH, Giannikopoulos P, Duncan SA, Wang J, Johansen CT, Brown JD, Plutzky J, Hegele RA, Glimcher LH, Lee AH. The transcription factor cyclic AMP-responsive element-binding protein H regulates triglyceride metabolism. Nat Med 2011;17:812–5.PubMedCrossrefGoogle Scholar

  • 77.

    Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H, Takei Y, Masuda M, Tanimura A, Harada N, Yamanaka-Okumura H, Takeda E. Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? PLoS One 2011;6:e22976.PubMedCrossrefGoogle Scholar

  • 78.

    Li Y, Wong K, Walsh K, Gao B, Zang M. Retinoic acid receptor β stimulates hepatic induction of fibroblast growth factor 21 to promote fatty acid oxidation and control whole-body energy homeostasis in mice. J Biol Chem 2013;288:10490–504.CrossrefPubMedGoogle Scholar

  • 79.

    Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem 2010;285:15668–73.PubMedCrossrefGoogle Scholar

  • 80.

    Adams AC, Astapova I, Fisher FM, Badman MK, Kurgansky KE, Flier JS, Hollenberg AN, Maratos-Flier E. Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner. J Biol Chem 2010;285:14078–82.CrossrefGoogle Scholar

  • 81.

    De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4 dependent induction of FGF21 during amino acid deprivation. Biochem J 2012;443:165–71.CrossrefPubMedGoogle Scholar

  • 82.

    Cyphert HA, Ge X, Kohan AB, Salati LM, Zhang Y, Hillgartner FB. Activation of the farnesoid X receptor induces hepatic expression and secretion of fibroblast growth factor 21. J Biol Chem 2012;287:25123–38.PubMedCrossrefGoogle Scholar

  • 83.

    Iizuka K, Takeda J, Horikawa Y. Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes. FEBS Lett 2009;583:2882–6.PubMedCrossrefGoogle Scholar

  • 84.

    Sánchez J, Palou A, Picó C. Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction. Endocrinology 2009;150:5341–50.CrossrefPubMedGoogle Scholar

  • 85.

    Hao L, Huang KH, Ito K, Sae-Tan S, Lambert JD, Ross AC. Fibroblast growth factor 21 (Fgf21) gene expression is elevated in the liver of mice fed a high-carbohydrate liquid diet and attenuated by a lipid emulsion but is not upregulated in the liver of mice fed a high-fat obesogenic diet. J Nutr 2016;146:184–90.CrossrefPubMedGoogle Scholar

  • 86.

    Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem 2006;281:28721–30.PubMedCrossrefGoogle Scholar

  • 87.

    Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 2015;4:51–7.CrossrefPubMedGoogle Scholar

  • 88.

    Wang ZQ, Yu Y, Zhang XH, Elizabeth Floyd Z, Boudreau A, Lian K, Cefalu WT. Comparing the effects of nano-sized sugarcane fiber with cellulose and psyllium on hepatic cellular signaling in mice. Int J Nanomedicine 2012;7:2999–3012.PubMedGoogle Scholar

  • 89.

    Villarroya J, Flachs P, Redondo-Angulo I, Giralt M, Medrikova D, Villarroya F, Kopecky J, Planavila A. Fibroblast growth factor-21 and the beneficial effects of long-chain n-3 polyunsaturated fatty acids. Lipids 2014;49:1081–9.PubMedCrossrefGoogle Scholar

  • 90.

    Mai K, Andres J, Biedasek K, Weicht J, Bobbert T, Sabath M, Meinus S, Reinecke F, Möhlig M, Weickert MO, Clemenz M, Pfeiffer AF, Kintscher U, Spuler S, Spranger J. Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21. Diabetes 2009;58:1532–8.CrossrefPubMedGoogle Scholar

  • 91.

    Yu J, Yu B, Jiang H, Chen D. Conjugated linoleic acid induces hepatic expression of fibroblast growth factor 21 through PPAR-α. Br J Nutr 2011;107:461–5.PubMedGoogle Scholar

  • 92.

    Li H, Gao Z, Zhang J, Ye X, Xu A, Ye J, Jia W. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes 2012;61:797–806.CrossrefPubMedGoogle Scholar

  • 93.

    Xia M, Erickson A, Yi X, Moreau R. Mapping the response of human fibroblast growth factor 21 (FGF21) promoter to serum availability and lipoic acid in HepG2 hepatoma cells. Biochim Biophys Acta 2016;1860:498–507.CrossrefPubMedGoogle Scholar

  • 94.

    Yi X, Pashaj A, Xia M, Moreau R. Reversal of obesity-induced hypertriglyceridemia by (R)-a-lipoic acid in ZDF (fa/fa) rats. Biochem Biophys Res Commun 2013;439:390–5.CrossrefGoogle Scholar

  • 95.

    Bae KH, Min AK, Kim JG, Lee IK, Park KG. Alpha lipoic acid induces hepatic fibroblast growth factor 21 expression via up-regulation of CREBH. Biochem Biophys Res Commun 2014;455:212–7.CrossrefPubMedGoogle Scholar

  • 96.

    Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E. A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 2009;297:E1197–204.PubMedCrossrefGoogle Scholar

  • 97.

    Nygaard EB, Møller CL, Kievit P, Grove KL, Andersen B. Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non-human primates (Macaca mulatta). Int J Obes 2014;38:183–91.CrossrefGoogle Scholar

  • 98.

    Fisher FM, Chui PC, Antonellis PJ, Bina HA, Kharitonenkov A, Flier JS, Maratos-Flier E. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 2010;59:2781–9.CrossrefPubMedGoogle Scholar

  • 99.

    McCarty MF. GCN2 and FGF21 are likely mediators of the protection from cancer, autoimmunity, obesity, and diabetes afforded by vegan diets. Med Hypotheses 2014;83:365–71.PubMedCrossrefGoogle Scholar

  • 100.

    Guo F, Cavener DR. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 2007;5:103–14.CrossrefPubMedGoogle Scholar

  • 101.

    Cheng Y, Meng Q, Wang C, Li H, Huang Z, Chen S, Xiao F, Guo F. Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue. Diabetes 2010;59:17–25.PubMedCrossrefGoogle Scholar

  • 102.

    Ables GP, Perrone CE, Orentreich D, Orentreich N. Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS One 2012;7:1–12.Google Scholar

  • 103.

    Lees EK, Król E, Grant L, Shearer K, Wyse C, Moncur E, Bykowska AS, Mody N, Gettys TW, Delibegovic M. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 2014;13:817–27.CrossrefPubMedGoogle Scholar

  • 104.

    Stone KP, Wanders D, Orgeron M, Cortez CC, Gettys TW. Mechanisms of increased in vivo insulin sensitivity by dietary methionine restriction in mice. Diabetes 2014;63:1–28.Google Scholar

  • 105.

    Morrison CD, Laeger T. Protein-dependent regulation of feeding and metabolism. Trends Endocrinol Metab 2015;26:256–62.CrossrefPubMedGoogle Scholar

  • 106.

    Ozaki Y, Saito K, Nakazawa K, Konishi M, Itoh N, Hakuno F, Takahashi S, Kato H, Takenaka A. Rapid increase in fibroblast growth factor 21 in protein malnutrition and its impact on growth and lipid metabolism. Br J Nutr 2015;114:1410–8.CrossrefPubMedGoogle Scholar

  • 107.

    Bielohuby M, Menhofer D, Kirchner H, Stoehr BJM, Muller TD, Stock P, Hempel M, Stemmer K, Pfluger PT, Kienzle E, Christ B, Tschöp MH, Bidlingmaier M. Induction of ketosis in rats fed low-carbohydrate, high-fat diets depends on the relative abundance of dietary fat and protein. Am J Physiol Endocrinol Metab 2011;300:E65–76.CrossrefPubMedGoogle Scholar

  • 108.

    Jiang Y, Rose AJ, Sijmonsma TP, Bröer A, Pfenninger A, Herzig S, Schmoll D, Bröer S. Mice lacking neutral amino acid transporter B0AT1 (Slc6a19) have elevated levels of FGF21 and GLP-1 and improved glycaemic control. Mol Metab 2015;4:406–17.CrossrefGoogle Scholar

  • 109.

    Wilson GJ, Lennox BA, She P, Mirek ET, Al Baghdadi RJT, Fusakio ME, Dixon JL, Henderson GC, Wek RC, Anthony TG. GCN2 is required to increase fibroblast growth factor 21 and maintain hepatic triglyceride homeostasis during asparaginase treatment. Am J Physiol Endocrinol Metab 2015;308:E283–93.PubMedCrossrefGoogle Scholar

  • 110.

    Shimizu N, Maruyama T, Yoshikawa N, Matsumiya R, Ma Y, Ito N, Tasaka Y, Kuribara-Souta A, Miyata K, Oike Y, Berger S, Schütz G, Takeda S, Tanaka H. A muscle-liver-fat signalling axis is essential for central control of adaptive adipose remodelling. Nat Commun 2015;6:6693.PubMedCrossrefGoogle Scholar

  • 111.

    Qiu H, Dong J, Hu C, Francklyn CS, Hinnebusch AG. The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation. EMBO J 2001;20:1425–38.PubMedCrossrefGoogle Scholar

  • 112.

    Anthony TG, McDaniel BJ, Byerley RL, McGrath BC, Cavener DR, McNurlan MA, Wek RC. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J Biol Chem 2004;279:36553–61.CrossrefPubMedGoogle Scholar

  • 113.

    Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF, Bell JC, Hettmann T, Leiden JM, Ron D. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003;11:619–33.CrossrefPubMedGoogle Scholar

  • 114.

    Shan J, Ord D, Ord T, Kilberg MS. Elevated ATF4 expression, in the absence of other signals, is sufficient for transcriptional induction via CCAAT enhancer-binding protein-activating transcription factor response elements. J Biol Chem 2009;284:21241–8.CrossrefPubMedGoogle Scholar

  • 115.

    Wan XS, Lu XH, Xiao YC, Lin Y, Zhu H, Ding T, Yang Y, Huang Y, Zhang Y, Liu YL, Xu ZM, Xiao J, Li XK. ATF4- and CHOP-dependent induction of FGF21 through endoplasmic reticulum stress. Biomed Res Int 2014;2014:807874.PubMedGoogle Scholar

  • 116.

    Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 2013;126(Pt 8):1713–9.CrossrefGoogle Scholar

  • 117.

    Cornu M, Oppliger W, Albert V, Robitaille AM, Trapani F, Quagliata L, Fuhrer T, Sauer U, Terracciano L, Hall MN. Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21. Proc Natl Acad Sci USA 2014;111:11592–9.CrossrefGoogle Scholar

  • 118.

    Monagas M, Urpi-Sarda M, Sánchez-Patán F, Llorach R, Garrido I, Gómez-Cordovés C, Andres-Lacueva C, Bartolomé B. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food Funct 2010;1:233–53.CrossrefGoogle Scholar

  • 119.

    Cardona F, Andrés-Lacueva C, Tulipani S, Tinahones FJ, Queipo-Ortuño MI. Benefits of polyphenols on gut microbiota and implications in human health. J Nutr Biochem 2013;24:1415–22.PubMedCrossrefGoogle Scholar

  • 120.

    Arranz S, Chiva-Blanch G, Valderas-Martínez P, Medina-Remón A, Lamuela-Raventós RM, Estruch R. Wine, beer, alcohol and polyphenols on cardiovascular disease and cancer. Nutrients 2012;4:759–81.CrossrefPubMedGoogle Scholar

  • 121.

    Dembinska-Kiec A, Mykkänen O, Kiec-Wilk B, Mykkänen H. Antioxidant phytochemicals against type 2 diabetes. Br J Nutr 2008;99E(Suppl):ES109–17.Google Scholar

  • 122.

    Xiao JB, Högger P. Dietary polyphenols and type 2 diabetes: current insights and future perspectives. Curr Med Chem 2015;22:23–38.PubMedGoogle Scholar

  • 123.

    Wang S, Moustaid-Moussa N, Chen L, Mo H, Shastri A, Su R, Bapat P, Kwun I, Shen CL. Novel insights of dietary polyphenols and obesity. J Nutr Biochem 2014;25:1–18.PubMedCrossrefGoogle Scholar

  • 124.

    Pan Q-R, Ren Y-L, Liu W-X, Hu Y-J, Zheng J-S, Xu Y, Wang G. Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. Nutr Res 2015;35:576–84.CrossrefPubMedGoogle Scholar

  • 125.

    Chen I-J, Liu C-Y, Chiu J-P, Hsu C-H. Therapeutic effect of high-dose green tea extract on weight reduction: a randomized, double-blind, placebo-controlled clinical trial. Clin Nutr 2016;35:592–9.PubMedCrossrefGoogle Scholar

  • 126.

    Ueno T, Torimura T, Nakamura T, Sivakumar R, Nakayama H, Otabe S, Yuan X, Yamada K, Hashimoto O, Inoue K, Koga H, Sata M. Epigallocatechin-3-gallate improves nonalcoholic steatohepatitis model mice expressing nuclear sterol regulatory element binding protein-1c in adipose tissue. Int J Mol Med 2009;24:17–22.PubMedGoogle Scholar

  • 127.

    Kim M-H, Kang K-S, Lee Y-S. The inhibitory effect of genistein on hepatic steatosis is linked to visceral adipocyte metabolism in mice with diet-induced non-alcoholic fatty liver disease. Br J Nutr 2010;104:1333–42.PubMedCrossrefGoogle Scholar

  • 128.

    Park HJ, Jung UJ, Lee MK, Cho SJ, Jung HK, Hong JH, Park YB, Kim SR, Shim S, Jung J, Choi MS. Modulation of lipid metabolism by polyphenol-rich grape skin extract improves liver steatosis and adiposity in high fat fed mice. Mol Nutr Food Res 2013;57:360–4.PubMedCrossrefGoogle Scholar

  • 129.

    Murase T, Misawa K, Minegishi Y, Aoki M, Ominami H, Suzuki Y, Shibuya Y, Hase T. Coffee polyphenols suppress diet-induced body fat accumulation by downregulating SREBP-1c and related molecules in C57BL/6J mice. Am J Physiol Endocrinol Metab 2011;300:E122–33.CrossrefPubMedGoogle Scholar

  • 130.

    Zang M, Xu S, Maitland-Toolan KA, Zuccollo A, Hou X, Jiang B, Wierzbicki M, Verbeuren TJ, Cohen RA. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes 2006;55:2180–91.PubMedCrossrefGoogle Scholar

  • 131.

    Hou X, Xu S, Maitland-Toolan KA, Sato K, Jiang B, Ido Y, Lan F, Walsh K, Wierzbicki M, Verbeuren TJ, Cohen RA, Zang M. SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase. J Biol Chem 2008;283:20015–26.CrossrefPubMedGoogle Scholar

  • 132.

    Rodriguez-Ramiro I, Vauzour D, Minihane AM. Polyphenols and non-alcoholic fatty liver disease: impact and mechanisms. Proc Nutr Soc 2016;75:47–60.PubMedCrossrefGoogle Scholar

  • 133.

    Zhang T, Yamamoto N, Yamashita Y, Ashida H. The chalcones cardamonin and flavokawain B inhibit the differentiation of preadipocytes to adipocytes by activating ERK. Arch Biochem Biophys 2014;554:44–54.PubMedCrossrefGoogle Scholar

  • 134.

    Monika P, Geetha A. The modulating effect of Persea americana fruit extract on the level of expression of fatty acid synthase complex, lipoprotein lipase, fibroblast growth factor-21 and leptin – a biochemical study in rats subjected to experimental hyperlipidemia and obesit. Phytomedicine 2015;22:939–45.CrossrefGoogle Scholar

  • 135.

    Tian L, Zeng K, Shao W, Yang BB, Fantus IG, Weng J, Jin T. Short-term curcumin gavage sensitizes insulin signaling in dexamethasone-treated C57BL/6 mice. J Nutr 2015;145:2300–7.CrossrefPubMedGoogle Scholar

  • 136.

    Song H, Zheng Z, Wu J, Lai J, Chu Q, Zheng X. White pitaya (Hylocereus undatus) juice attenuates insulin resistance and hepatic steatosis in diet-induced obese mice. PLoS One 2016;11:e0149670.PubMedCrossrefGoogle Scholar

  • 137.

    Yu Y, Zhang XH, Ebersole B, Ribnicky D, Wang ZQ. Bitter melon extract attenuating hepatic steatosis may be mediated by FGF21 and AMPK/Sirt1 signaling in mice. Sci Rep 2013;3:3142.PubMedCrossrefGoogle Scholar

  • 138.

    Chen W-W, Li L, Yang G-Y, Li K, Qi X-Y, Zhu W, Tang Y, Liu H, Boden G. Circulating FGF-21 levels in normal subjects and in newly diagnose patients with Type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2008;116:65–8.PubMedGoogle Scholar

  • 139.

    Zhang X1, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008;57:1246–53.PubMedCrossrefGoogle Scholar

  • 140.

    Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, DeFronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 2009;32:1542–6.PubMedCrossrefGoogle Scholar

  • 141.

    Reinehr T, Woelfle J, Wunsch R, Roth CL. Fibroblast growth factor 21 (FGF-21) and its relation to obesity, metabolic syndrome, and nonalcoholic fatty liver in children: a longitudinal analysis. J Clin Endocrinol Metab 2012;97:2143–50.PubMedCrossrefGoogle Scholar

  • 142.

    Reinehr T, Karges B, Meissner T, Wiegand S, Fritsch M, Holl RW, Woelfle J. Fibroblast growth factor 21 and fetuin-a in obese adolescents with and without type 2 diabetes. J Clin Endocrinol Metab 2015;100:3004–10.PubMedCrossrefGoogle Scholar

  • 143.

    Reinehr T, Roth CL, Woelfle J. Fibroblast growth factor 21 (FGF-21) in obese children: no relationship to growth, IGF-1, and IGFBP-3. Horm Mol Biol Clin Invest 2017;30:20150074.Google Scholar

  • 144.

    Hanks LJ, Casazza K, Ashraf AP, Wallace S, Gutiérrez OM. Fibroblast growth factor-21, body composition, and insulin resistance in pre-pubertal and early pubertal males and females. Clin Endocrinol 2015;82:550–6.CrossrefGoogle Scholar

  • 145.

    Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, Pan X, Bao Y, Xiang K, Xu A, Jia W. Fibroblast growth factor 21 levels are increased in nonalcoholic fatty liver disease patients and are correlated with hepatic triglyceride. J Hepatol 2010;53:934–40.CrossrefPubMedGoogle Scholar

  • 146.

    Davis RL, Liang C, Edema-Hildebrand F, Riley C, Needham M, Sue CM. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology 2013;81:1819–26.PubMedCrossrefGoogle Scholar

  • 147.

    Kralisch S, Tönjes A, Krause K, Richter J, Lossner U, Kovacs P, Ebert T, Blüher M, Stumvoll M, Fasshauer M. Fibroblast growth factor-21 serum concentrations are associated with metabolic and hepatic markers in humans. J Endocrinol 2013;216:135–43.PubMedCrossrefGoogle Scholar

  • 148.

    Hanks LJ, Gutiérrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K. Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol 2015;2:72–82.Google Scholar

  • 149.

    Gälman C, Lundåsen T, Kharitonenkov A, Bina HA, Eriksson M, Hafström I, Dahlin M, Amark P, Angelin B, Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab 2008;8:169–74.CrossrefPubMedGoogle Scholar

  • 150.

    Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man. J Clin Endocrinol Metab 2009;94:3594–601.CrossrefPubMedGoogle Scholar

  • 151.

    Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y, Lee H, Catana C, Klibanski A, Patwari P, Steinhauser ML. FGF21 and the late adaptive response to starvation in humans. J Clin Invest 2015;125:4601–11.CrossrefPubMedGoogle Scholar

  • 152.

    Qin Y, Zhou Y, Chen SH, Zhao XL, Ran L, Zeng XL, Wu Y, Chen JL, Kang C, Shu FR, Zhang QY, Mi MT. Fish oil supplements lower serum lipids and glucose in correlation with a reduction in plasma fibroblast growth factor 21 and prostaglandin E2 in nonalcoholic fatty liver disease associated with hyperlipidemia: a randomized clinical trial. PLoS One 2015;10:1–13.Google Scholar

  • 153.

    Ejaz A, Martinez-Guino L, Goldfine AB, Ribas-Aulinas F, De Nigris V, Ribó S, Gonzalez-Franquesa A, Garcia-Roves PM, Li E, Dreyfuss JM, Gall W, Kim JK, Bottiglieri T, Villarroya F, Gerszten RE, Patti ME, Lerin C. Dietary betaine supplementation increases Fgf21 levels to improve glucose homeostasis and reduce hepatic lipid accumulation in mice. Diabetes 2016;65:902–12.PubMedCrossrefGoogle Scholar

  • 154.

    Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, Holland J, Hembree JL, Smiley D, Gelfanov V, Krishna R, Arafat AM, Konkar A, Belli S, Kapps M, Woods SC, Hofmann SM, D’Alessio D, Pfluger PT, Perez-Tilve D, Seeley RJ, Konishi M, Itoh N, Kharitonenkov A, Spranger J, DiMarchi RD, Tschöp MH. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 2013;62:1453–63.CrossrefPubMedGoogle Scholar

About the article

Received: 2016-07-01

Accepted: 2016-07-21

Published Online: 2016-09-01

Funding: Authors state no funding involved.

Conflict of interest: Authors state no conflict of interest.

Material and methods: Informed consent: Informed consent is not applicable.

Ethical approval: The conducted research is not related to either human or animals use.

Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 30, Issue 1, 20160034, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2016-0034.

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